Ultrasonic controllable crystallization method for freeze dryer

Abstract

The invention discloses an ultrasonic controllable crystallization method for a freeze dryer. The ultrasonic controllable crystallization method specifically comprises the following steps: placing liquid to be freeze-dried in an action area of an ultrasonic generating device in the freeze dryer; freeze-drying parameters are set, and the freeze dryer runs to a set working condition; under the set working condition, the ultrasonic generating device is started to vibrate the liquid to be freeze-dried, and crystallization is induced; the crystallization state of the liquid to be freeze-dried is monitored, and the vibration parameters of the ultrasonic generating device are adjusted in real time according to the crystallization state. The crystallization process can be accurately controlled, and the crystallization uniformity is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of freeze-drying, and particularly to an ultrasonic controllable crystallization method for a freeze-dryer. Background Art

[0002] In the freeze-drying process, the control of the crystallization process has an important impact on the product quality. Currently, freeze-dryers usually adopt a temperature control method to achieve the freezing and crystallization of liquids, but this method has several technical defects: it is difficult to ensure the crystallization uniformity, resulting in unstable product quality; it is difficult to precisely control the crystal size, affecting the reconstitution performance of the product; the crystallization speed is relatively slow, prolonging the production cycle.

[0003] Therefore, there is an urgent need to propose an ultrasonic controllable crystallization method for a freeze-dryer to solve the above problems. Summary of the Invention

[0004] The purpose of the present invention is to propose an ultrasonic controllable crystallization method for a freeze-dryer, which can precisely control the crystallization process and improve the crystallization uniformity.

[0005] To solve the above technical problems, the present invention provides an ultrasonic controllable crystallization method for a freeze-dryer, which specifically includes the following steps:

[0006] Place the liquid to be freeze-dried within the action area of the ultrasonic generating device in the freeze-dryer;

[0007] Set the freeze-drying parameters and operate the freeze-dryer to the set working conditions;

[0008] Under the set working conditions, start the ultrasonic generating device to vibrate the liquid to be freeze-dried to induce crystallization;

[0009] Monitor the crystallization state of the liquid to be freeze-dried, and adjust the vibration parameters of the ultrasonic generating device in real time according to the crystallization state.

[0010] Further, the freeze-drying parameters include temperature and pressure; the temperature range is between -60 °C and -30 °C, and the pressure range is between 10 mbar and 2000 mbar.

[0011] Further, the monitoring of the crystallization state of the liquid to be freeze-dried specifically includes: optically monitoring or acoustically monitoring the crystallization state of the liquid to be freeze-dried.

[0012] Further, the optical monitoring includes: transferring the sample to an electron microscope through a cryogenic transfer device; collecting the sample image using the electron microscope; obtaining the morphological characteristics, average particle size, and particle size distribution of the crystals through image analysis;

[0013] Judge the crystallization state according to the preset crystal morphology requirements, target particle size range, and distribution standard deviation.

[0014] Further, the determination of the crystallization state specifically includes: judging the degree of regularity of the crystal morphology, and counting the proportion of irregular crystals; calculating the deviation between the average crystal particle size and a preset target range; calculating the standard deviation of the crystal particle size distribution; when the proportion of irregular crystals, the particle size deviation, or the standard deviation exceeds their respective preset thresholds, it is determined that the crystallization state is abnormal.

[0015] Further, during the acoustic monitoring process, a pair of ultrasonic transducers are arranged in the freeze dryer, one of which serves as a transmitter and the other as a receiver; measuring the attenuation coefficient of the ultrasonic wave during propagation; judging the crystallization process according to the change of the attenuation coefficient.

[0016] Further, the attenuation coefficient is calculated by the following formula: where α is the attenuation coefficient, x is the ultrasonic propagation distance, I 0 is the initial intensity, I is the intensity after passing through the distance x, and ln is the natural logarithm.

[0017] Further, detecting the change trend of the attenuation coefficient; when it is detected that the growth rate of the attenuation coefficient is greater than a preset threshold, it is determined that crystallization is in progress; when it is detected that the change rate of the attenuation coefficient is less than a preset threshold, it is determined that crystallization is basically completed.

[0018] Further, the vibration parameters include frequency and power; the range of the frequency is between 10 and 1000 kHz, and the power range is between 1 and 100 W.

[0019] Further, the determination process of the vibration parameters includes:

[0020] Keeping the power unchanged, conducting crystallization tests at different frequencies to obtain the optimal frequency;

[0021] Keeping the optimal frequency unchanged, conducting crystallization tests at different powers to obtain the optimal power;

[0022] Recording the crystal size and uniformity of each test;

[0023] Determining the optimal frequency and the optimal power according to the comparison results of the crystal size and uniformity to obtain the vibration parameters.

[0024] Through the above technical solutions, the present invention has the following beneficial effects:

[0025] By introducing ultrasonic vibration to induce crystallization during the freeze-drying process and monitoring the crystallization state in real time, the crystallization process can be precisely controlled to improve the freeze-drying effect; by adjusting the vibration parameters in real time, the stability and controllability of the crystallization process can be ensured, and the quality of the freeze-dried product can be significantly improved.

[0026] Through the combination of optical monitoring and acoustic monitoring, comprehensive monitoring of the crystallization state is achieved; through preset parameter ranges and threshold judgments, the reliability of the crystallization process is ensured; through a systematic method for determining vibration parameters, the optimization efficiency of process parameters is improved, making the entire freeze-drying process more intelligent and automated. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a flowchart of the ultrasonic controllable crystallization method for a freeze dryer in an embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0028] The following will describe in more detail an ultrasonic controllable crystallization method for a freeze dryer according to the present invention with reference to the accompanying drawings, in which the preferred embodiments of the present invention are shown. It should be understood that those skilled in the art can modify the present invention described herein while still achieving the advantageous effects of the present invention. Therefore, the following description should be understood as a broad guidance for those skilled in the art and not as a limitation to the present invention.

[0029] In the following paragraphs, the present invention will be described more specifically by way of example with reference to the accompanying drawings. The advantages and features of the present invention will be clearer according to the following description. It should be noted that the drawings are all in a very simplified form and use non-precise scales, only for the purpose of facilitating and clearly assisting in explaining the objectives of the embodiments of the present invention.

[0030] As Figure 1 shown, an embodiment of the present invention provides an ultrasonic controllable crystallization method for a freeze dryer, which specifically includes the following steps:

[0031] S1. Place the liquid to be freeze-dried within the action area of the ultrasonic generating device in the freeze dryer;

[0032] S2. Set the freeze-drying parameters and operate the freeze dryer to the set working conditions;

[0033] S3. Under the set working conditions, start the ultrasonic generating device to vibrate the liquid to be freeze-dried to induce crystallization; and

[0034] S4. Monitor the crystallization state of the liquid to be freeze-dried and adjust the vibration parameters of the ultrasonic generating device in real time according to the crystallization state.

[0035] In this embodiment, ultrasonic vibration is used to induce crystallization, which can improve the controllability of crystallization and also overcome the limitations of traditional temperature-dependent control. And through real-time monitoring and adjustment, real-time monitoring and dynamic adjustment of the crystallization process can be achieved, so that deviations can be corrected in a timely manner, the stability of the crystallization quality can be ensured, and the controllability of the crystallization process can also be enhanced.

[0036] In one embodiment, the lyophilization parameters include temperature and pressure. As is known to those skilled in the art, the setting of the lyophilization parameters needs to be adjusted according to the characteristics of the liquid to be lyophilized, and different substances may require different parameter settings. Therefore, the lyophilization parameters also include other embodiments besides this embodiment.

[0037] In a specific example, the temperature range is between -60 and -30 °C, and the pressure range is between 10 and 2000 mbar. Specifically, for protein substances, a temperature of -40 °C and a pressure of 1000 mbar can be selected; for polysaccharide substances, a temperature of -30 °C and a pressure of 1500 mbar can be selected. As is known to those skilled in the art, the temperature and pressure can be set according to actual needs, and it also includes other embodiments besides this embodiment. This embodiment ensures that the crystallization process proceeds under the most suitable conditions by setting a reasonable temperature and pressure range, improving the crystallization effect.

[0038] Preferably, the crystallization state includes crystal size and uniformity. In a specific example, the crystal size can be measured by an online particle size analyzer, and the uniformity can be evaluated by microscopic observation or optical analysis methods. In one embodiment, the vibration parameters include frequency and power. Further, the frequency range is between 10 and 1000 kHz, and the power range is between 1 and 100 W. Specifically, for different types of liquids to be lyophilized, different combinations of frequency and power can be selected: for small molecule drugs, a frequency of 100 kHz and a power of 20 W can be selected; for macromolecular proteins, a frequency of 50 kHz and a power of 30 W can be selected. As is known to those skilled in the art, the frequency and power can be set according to actual needs. This embodiment can provide a suitable parameter adjustment range, enabling the operator to flexibly adjust within a reasonable range to meet the needs of different materials.

[0039] In step S4, monitoring the crystallization state of the liquid to be lyophilized specifically includes: optically or acoustically monitoring the crystallization state of the liquid to be lyophilized.

[0040] In one embodiment, the optical monitoring includes: transferring the sample to an electron microscope through a cryogenic transfer device; collecting sample images using the electron microscope; obtaining the morphological characteristics, average particle size, and particle size distribution of the crystals through image analysis;

[0041] Judging the crystallization state according to the preset crystal morphology requirements, target particle size range, and distribution standard deviation.

[0042] Further, the determination of the crystallization state specifically includes: judging the degree of regularity of the crystal morphology, and counting the proportion of irregular crystals; calculating the deviation between the average crystal particle size and the preset target range; calculating the standard deviation of the crystal particle size distribution; when the proportion of irregular crystals, the particle size deviation or the standard deviation exceeds their respective preset thresholds, it is determined that the crystallization state is abnormal.

[0043] In a specific example, in an ideal crystallization state, the crystals should exhibit regular geometric shapes, such as cubes, hexahedrons, etc. If the crystal morphology shows irregularities, there are a large number of agglomerations, distortions or breakages, and the proportion of irregular crystals exceeds 10%, it indicates that the crystallization process does not meet the expectations. Secondly, according to the specific requirements of the product, the target particle size range of the crystals is preset in advance. Taking some freeze-dried drug products as an example, the target crystal particle size is usually set between 50 and 100 microns. When it is monitored that the average particle size of the crystals deviates from the target range by more than 20%, or the standard deviation of the particle size distribution is greater than 15 microns, this means that the crystallization state is uneven and the process parameters need to be intervened.

[0044] In another embodiment, during the acoustic monitoring process, a pair of ultrasonic transducers are arranged in the freeze-dryer, one of which is used as a transmitter and the other as a receiver; the attenuation coefficient of the ultrasonic wave during propagation is measured; the crystallization process is judged according to the change of the attenuation coefficient.

[0045] Among them, the attenuation coefficient is calculated by the following formula: Among them, α is the attenuation coefficient, x is the ultrasonic wave propagation distance, I 0 is the initial intensity, I is the intensity after passing through the distance x, and l n is the natural logarithm.

[0046] Further, the change trend of the attenuation coefficient is detected; when it is detected that the growth rate of the attenuation coefficient is greater than the preset threshold, it is determined that crystallization is in progress; when it is detected that the change rate of the attenuation coefficient is less than the preset threshold, it is determined that crystallization is basically completed. It can be seen that in this embodiment, during the crystallization process, this measurement process is continuously repeated to observe the change of the attenuation coefficient. If the attenuation coefficient gradually increases, it indicates that the crystals are continuously forming and increasing; when the attenuation coefficient reaches a relatively stable value, it may indicate that the crystallization process is basically over.

[0047] In a specific example, when monitoring the crystallization state by ultrasonic intensity using the above attenuation coefficient calculation formula, it is first necessary to accurately measure the initial intensity I of the ultrasonic wave 0 and the intensity I after passing through a certain distance x in the crystallization medium. Measure the initial intensity I 0When it is necessary to ensure the stable performance of the ultrasonic transmitting device and measure it without interference factors such as crystallization. For the propagation distance x, it needs to be accurately measured. In the actual device, x can be determined by designing a fixed ultrasonic propagation path length. When measuring the intensity I after propagation, the influence of the crystallization state on ultrasonic waves needs to be considered. During the crystallization process, the growth of crystals will cause changes in the physical properties of the medium (such as density, elastic modulus, etc.), thereby affecting the propagation and intensity of ultrasonic waves. For example, when the crystal particles increase, the scattering and absorption of ultrasonic waves will increase, and the intensity I will decrease. By measuring I at different times and combining the known I 0 and x, the attenuation coefficient can be calculated using the above formula, and then the crystallization state can be analyzed.

[0048] In step S32, the determination process of the vibration parameters specifically includes the following steps (i.e., the method of controlling variables): keeping the power unchanged, conducting crystallization tests at different frequencies to obtain the optimal frequency; keeping the optimal frequency unchanged, conducting crystallization tests at different powers to obtain the optimal power; determining the vibration parameters according to the optimal frequency and the optimal power. This parameter optimization method improves the repeatability of the crystallization process. In addition, in this embodiment, the optimal vibration parameters are determined by the method of fixing one parameter to optimize another parameter, which can systematically find the optimal parameter combination and improve the repeatability of the results.

[0049] In this embodiment, an online particle size analyzer is used to monitor and record the change in crystal size during the crystallization test. Specifically, a laser diffraction type online particle size analyzer can be selected, with a measurement range of 0.1 - 1000 μm, and the sampling interval can be set to 5 - 10 seconds. Using an online particle size analyzer to monitor the change in crystal size in this embodiment can achieve precise monitoring of the crystallization process, provide objective data support, and contribute to the optimization of process parameters and quality control.

[0050] Preferably, the crystal size and uniformity are recorded each time the test is conducted, and the optimal frequency and the optimal power are determined by comparison. In a specific example, 3 - 5 frequency gradients and power gradients can be set for testing, and each parameter combination is tested 3 times, and the average value is taken for comparison.

[0051] Therefore, this embodiment can not only improve the crystallization uniformity and reduce the product quality difference; but also accelerate the crystallization process, shorten the freeze - drying cycle, and improve production efficiency; it can also improve the crystal quality, reduce impurities and defects; and is simple and flexible to operate with strong adaptability.

[0052] In a specific example, the adjustment of vibration parameters can be carried out by means of DOE tools for multi-factor experimental design. The upper and lower limits are set for two factors, namely vibration frequency and power, and multiple groups of experimental conditions are obtained by inputting them into the software. Then, group-by-group tests are conducted according to the obtained experimental conditions. The obtained experimental results, such as particle size and the proportion of appropriate particle size, are input into the DOE tool. After all the results are input, a set of optimal experimental conditions can be obtained through the software. Currently, no suitable real-time feedback mechanism has been retrieved. Only by continuously modifying the experimental parameters based on the results obtained from multiple experiments can we approach the optimal conditions.

[0053] In this embodiment, the liquid to be freeze-dried is, for example, protein drugs, sodium chloride solution, mannitol solution, and vegetable juice.

[0054] Example 1

[0055] A certain amount of protein drugs is placed in the freeze-drying chamber. Specifically, for example, 100 ml of human albumin solution with a concentration of 10 mg / ml is placed in the stainless-steel tray of the freeze-dryer. The frequency of the ultrasonic vibration device is set to 50 kHz, and the power is 40 W. Under the freeze-drying conditions of a temperature of -40 °C and a pressure of 1000 mbar, the ultrasonic vibration device is started for a duration of 5 minutes to induce crystal formation. Then, the ultrasonic is stopped. By using an online particle size analyzer, it is found that larger crystals are formed, for example, with an average particle size of about 200 μm, which does not match the expectation. Subsequently, the frequency is increased to 500 kHz, and the power is reduced to 20 W (the frequency and power here are the optimal frequency and optimal power obtained by the above method of controlling variables). Under the same freeze-drying conditions, the ultrasonic vibration device is started for a duration of 5 minutes, and the crystal size after adjustment can be well controlled. For example, the average particle size is reduced to 50 μm, the particle size distribution range is narrowed to 30 - 70 μm, and the stability of the active ingredient is also significantly improved. After measurement, the protein activity retention rate reaches more than 95%.

[0056] Example 2

[0057] Place a 3% sodium chloride solution in a freeze dryer. Specifically, place 200 ml of the prepared sodium chloride solution in a stainless-steel tray equipped with a temperature sensor. Set the frequency of the ultrasonic vibration device to 20 kHz and the power to 20 W. Start the ultrasonic vibration device under freeze-drying conditions of -40 °C and 1000 mbar, and vibrate continuously for 3 minutes to induce crystal formation. Then stop the ultrasonic wave, and use an online particle size analyzer to record the particle size. For example, the average particle size is measured to be 150 μm. Subsequently, increase the frequency to 30 kHz and the power to 40 W (the frequency and power here are the optimal frequency and optimal power obtained by the above-mentioned control variable method). Start the ultrasonic vibration device under the same freeze-drying conditions for 3 minutes. After adjustment, the particle size decreases. For example, the average particle size drops to 80 μm, and 90% of the crystals are distributed in the range of 60 - 100 μm, improving the product's rehydration property. The rehydration time is shortened from the original 3 minutes to 1 minute.

[0058] Example 3

[0059] Place a certain amount of 5% mannitol solution in a freeze dryer. For example, specifically place 150 mL of mannitol solution filtered through a 0.22 μm filter membrane in a pre-cooled stainless-steel tray. Set the frequency of the ultrasonic vibration device to 20 kHz and the power to 10 W. Start the ultrasonic vibration device at -40 °C and 1000 mbar for 5 minutes to induce crystal formation (if the crystal size does not meet the expectation, it can also be adjusted according to the methods in Example 1 and Example 2, that is, the optimal frequency and optimal power obtained by the above-mentioned control variable method to adjust the vibration parameters). Then, stop the ultrasonic vibration device and enter the conventional freeze-drying step: for example, specifically, the temperature in the primary drying stage is -30 °C, the pressure is 100 mbar, and it lasts for 12 hours; in the secondary drying stage, the temperature rises to 20 °C, the pressure is maintained at 100 mbar, and it lasts for 6 hours. The final product has a uniform crystal structure. Under a microscope, the crystals are needle-shaped, with an average particle size of 60 μm. The product has good rehydration property and can be completely dissolved in only 30 seconds of rehydration time.

[0060] Example 4

[0061] Place the vegetable juice in a freeze dryer. For example, specifically, place 300 ml of homogenized carrot juice in a stainless-steel tray with a temperature probe after filtering it through a 0.45 μm filter membrane. Set the frequency of the ultrasonic vibration device to 30 kHz and the power to 15 W. Start the ultrasonic vibration device under the conditions of a temperature of -45°C and a pressure of 1000 mbar, and vibrate continuously for 3 minutes to control the crystal size (if the crystal size does not meet the expectations, it can also be adjusted according to the methods in Example 1 and Example 2, that is, by adjusting the vibration parameters with the optimal frequency and optimal power obtained by the above-mentioned control variable method). For example, after a freeze-drying process of primary sublimation (-30°C, 50 mbar, 16 hours) and secondary sublimation (10°C, 50 mbar, 8 hours), the product can preserve its original flavor and nutritional components, the retention rate of β-carotene reaches more than 90%, the moisture content of the finished product is less than 3%, and the rehydrated solution is clear and transparent without precipitation.

[0062] Through the verification of the above examples, in this example, by the control variable method, the power is fixed, and crystallization tests are carried out at different frequencies to obtain the optimal frequency; the optimal frequency is fixed, and crystallization tests are carried out at different powers to obtain the optimal power; finally, the optimal vibration parameter combination, that is, the optimal frequency and optimal power, is determined according to the test results. The experimental results of the above four examples show that the ultrasonic controllable crystallization method provided in this example can effectively control the crystallization process, improve the crystallization uniformity, and optimize the product quality. Different materials can obtain the best crystallization effect by adjusting the frequency and power parameters of the ultrasonic vibration device. Therefore, compared with the conventional freeze-drying process method, the freezing time is significantly shortened and the crystal form is more regular in this example.

[0063] In summary, the ultrasonic controllable crystallization method for a freeze dryer proposed by the present invention has the following advantages:

[0064] By introducing ultrasonic vibration to induce crystallization during the freeze-drying process and monitoring the crystallization state in real time, the crystallization process can be precisely controlled and the freeze-drying effect can be improved; by adjusting the vibration parameters in real time, the stability and controllability of the crystallization process can be ensured, and the quality of the freeze-dried product can be significantly improved.

[0065] Through the combination of optical monitoring and acoustic monitoring, a comprehensive monitoring of the crystallization state is achieved; through preset parameter ranges and threshold judgments, the reliability of the crystallization process is ensured; through a systematic method for determining vibration parameters, the optimization efficiency of process parameters is improved, making the entire freeze-drying process more intelligent and automated.

[0066] Obviously, those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these modifications and variations.

Claims

1. An ultrasonic controlled crystallization method for a freeze dryer, characterized in that: The details include: The liquid to be freeze-dried is placed in the action area of ​​the ultrasonic generator in the freeze dryer; Setting freeze-drying parameters and running the freeze dryer to set operating conditions; Under the set working conditions, starting the ultrasonic generator to vibrate the liquid to be freeze-dried to induce crystallization; The crystallization state of the liquid to be freeze-dried is monitored, and the vibration parameters of the ultrasonic generating device are adjusted in real time according to the crystallization state.

2. The ultrasonic controlled crystallization method for freeze dryer according to claim 1, characterized in that: The freeze-drying parameters include temperature and pressure; the temperature range is between -60 and -30°C, and the pressure range is between 10 and 2000 mbar.

3. The ultrasonic controlled crystallization method for freeze dryer according to claim 2, characterized in that: The monitoring of the crystallization state of the liquid to be freeze-dried specifically includes: optically monitoring or acoustically monitoring the crystallization state of the liquid to be freeze-dried.

4. The ultrasonic controlled crystallization method for freeze dryer according to claim 3, characterized in that: The optical monitoring includes: transferring the sample to an electron microscope through a low-temperature transfer device; collecting sample images using the electron microscope; obtaining the morphological characteristics, average particle size and particle size distribution of the crystal through image analysis; and judging the crystallization state according to preset crystal morphology requirements, target particle size range and distribution standard deviation.

5. The ultrasonic controlled crystallization method for freeze dryer according to claim 4, characterized in that: The judgment of the crystallization state specifically includes: judging the regularity of the crystal morphology and counting the proportion of irregular crystals; calculating the deviation between the average crystal particle size and the preset target range; calculating the standard deviation of the crystal particle size distribution; when the proportion of irregular crystals, particle size deviation or standard deviation exceeds the respective preset thresholds, the crystallization state is judged to be abnormal.

6. The ultrasonic controlled crystallization method for freeze dryer according to claim 3, characterized in that: During the acoustic monitoring process, a pair of ultrasonic transducers are arranged in the freeze dryer, one of which serves as a transmitter and the other as a receiver; the attenuation coefficient of ultrasonic waves during propagation is measured; and the crystallization process is determined based on the change in the attenuation coefficient.

7. The ultrasonic controlled crystallization method for freeze dryer according to claim 6, characterized in that: The attenuation coefficient is calculated by the following formula: Among them, α is the attenuation coefficient, x is the ultrasonic propagation distance, I0 is the initial intensity, I is the intensity after the distance x, and ln is the natural logarithm.

8. The ultrasonic controlled crystallization method for freeze dryer according to claim 7, characterized in that: Detect the changing trend of the attenuation coefficient; when it is detected that the growth rate of the attenuation coefficient is greater than a preset threshold, determine that crystallization is in progress; when it is detected that the change rate of the attenuation coefficient is less than a preset threshold, determine that crystallization is basically completed.

9. The ultrasonic controlled crystallization method for freeze dryer according to claim 1, characterized in that: The vibration parameters include frequency and power; the frequency ranges from 10 to 1000 kHz, and the power ranges from 1 to 100W.

10. The ultrasonic controlled crystallization method for freeze dryer according to claim 9, characterized in that: The vibration parameter determination process includes: Keeping the power constant, performing crystallization tests at different frequencies to obtain the optimal frequency; Keeping the optimal frequency unchanged, performing crystallization tests at different powers to obtain the optimal power; Record the crystal size and uniformity for each test; The optimal frequency and the optimal power are determined according to the comparison results of the crystal size and uniformity to obtain the vibration parameters.

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