An ion crosslinking receiving bath for accelerating interface penetration and its preparation method and application

Abstract

The application discloses an ion crosslinking receiving bath for accelerating interface penetration and a preparation method and application thereof, and belongs to the technical field of gel microsphere preparation, and comprises the following steps: preparing a separation bath: Span 80 is dissolved in fresh fish oil to prepare the separation bath; preparing a coagulation bath: a CaCl2 aqueous solution is prepared and vacuum degassing is performed to prepare the coagulation bath; and preparing a degassed emulsification receiving bath: the separation bath and the coagulation bath are mixed, and emulsification is performed after mixing to obtain the ion crosslinking receiving bath. The ion crosslinking receiving bath for accelerating interface penetration and the preparation method and application thereof are used, the coagulation bath is subjected to vacuum degassing treatment, the hydrophobic coalescence phenomenon caused by micro-bubbles in an oil-water system is effectively inhibited, a durable emulsification transition layer is formed, the oil-water interface energy barrier is greatly reduced, liquid drops can directly penetrate the phase interface into the lower water phase to complete crosslinking by relying on the self weight, and the defect of liquid drop suspension fusion in a conventional receiving bath is completely overcome.

Description

Technical Field

[0001] This invention relates to the field of gel microsphere preparation technology, and in particular to an ion crosslinking receiving bath for accelerating interfacial penetration, its preparation method, and its application. Background Technology

[0002] In the field of microsphere / gel sphere preparation, the method of forming small droplets by inserting and withdrawing needles into the oil phase is widely used due to its low cost and controllable size. However, this technology faces a key interface science challenge: polymer droplets formed by pectin or sodium alginate are significantly hindered by interfacial tension when crossing the oil-water phase interface, making it difficult for them to stably enter the lower aqueous phase coagulation bath to complete ionic cross-linking.

[0003] To address the aforementioned interface barrier problem, existing microfluidic technologies typically employ forced release of Ca. 2+ Strategies such as adding metal chelating agents, acidifying the oil phase, or introducing organic reagents partially miscible with water (e.g., dimethyl carbonate, DMC) can promote phase transfer to some extent. However, these methods all involve the introduction of additional chemical reagents and involve relatively harsh reaction conditions. This not only makes it difficult to meet the requirements for biocompatible manufacturing under neutral and mild environments but also poses safety risks in biomedical applications. Therefore, how to effectively weaken the oil-water interfacial energy barrier, accelerate the evacuation of the oil film from the droplet surface, and achieve stable ionic crosslinking under mild conditions without harsh chemical treatment has become a pressing technical challenge in this field. Summary of the Invention

[0004] The purpose of this invention is to provide an ion crosslinking receiving bath that accelerates interface penetration, its preparation method, and its application. By performing vacuum degassing on the coagulation bath, the hydrophobic aggregation phenomenon caused by microbubbles in the oil-water system is effectively suppressed, forming a durable emulsion transition layer. This significantly reduces the energy barrier at the oil-water interface, allowing droplets to directly penetrate the phase interface by their own weight and enter the lower aqueous phase to complete crosslinking, thus completely overcoming the defect of droplet suspension and fusion in conventional receiving baths.

[0005] To achieve the above objectives, the present invention provides a method for preparing an ion crosslinking receiving bath that accelerates interfacial penetration, comprising the following steps: S1. Preparation of separation bath: Dissolve Span 80 in fresh fish oil to prepare a separation bath. The volume concentration of Span 80 in fresh fish oil is 0.01-0.2%, and the amount of fresh fish oil used is 5-15 mL. S2. Preparation of coagulation bath: Prepare CaCl2 aqueous solution and degas under vacuum to obtain coagulation bath; S3. Preparation of degassing emulsification receiving bath: Mix the separation bath and the coagulation bath, and then emulsify the mixture to obtain the degassing emulsification receiving bath, i.e., the ion crosslinking receiving bath.

[0006] Preferably, in S1, the volume concentration of Span 80 in fresh fish oil is 0.05%.

[0007] Preferably, in S2, the mass-volume percentage of the CaCl2 aqueous solution is 2.5%, and the amount used is 20-40 mL.

[0008] Preferably, in S2, the parameters for vacuum degassing are: vacuum pressure of 10-50 kPa and degassing time of 10-60 min, until no new bubbles are generated in the solution.

[0009] Preferably, in S2, the vacuum pressure is 30 kPa and the degassing time is 30 min.

[0010] Preferably, in S3, the volume ratio of the separation bath to the coagulation bath is (2-4):1, and emulsification is performed using an ultrasonic disruptor with the following parameters: working power 300W, running for 2 seconds, pausing for 1 second, and working time 1 minute.

[0011] A visible, diffuse flexible phase interface is formed in the receiving bath, and the emulsion transition layer can remain stable for more than 4 hours.

[0012] An ion crosslinking receiving bath for accelerating interfacial penetration is prepared using the above-described method for preparing an ion crosslinking receiving bath for accelerating interfacial penetration.

[0013] An application of an ion crosslinking receiving bath to accelerate interfacial penetration: The aforementioned ion crosslinking receiving bath to accelerate interfacial penetration is applied to the continuous manufacturing of gel spheres.

[0014] Fish oil is rich in polyunsaturated fatty acids, and the cis configuration of its double bonds reduces intermolecular dispersion. Its relatively low viscosity and density facilitate rapid sedimentation after droplet formation. Fish oil has a lower polarity difference with water than edible oils such as medium-chain fatty acids, resulting in lower oil-water interfacial tension. This increases the probability of interfacial wetting of droplets from the aqueous gel precursor solution in the fish oil-water emulsion.

[0015] Removing the dissolved gas from the metal salt aqueous solution suppresses the hydrophobic aggregation phenomenon caused by microbubbles in the oil-water dispersion system, thus significantly extending the duration of the emulsion state in the absence of surfactants.

[0016] In this receiving bath, the gel precursor liquid droplets are more likely to embed into the flexible transition layer, increasing the probability of forming local contact with the aqueous phase, thereby accelerating the surface emulsification rate and completing ionic cross-linking.

[0017] A trace amount of Span 80 is used to help maintain the stability of the emulsion transition layer. At this concentration, Span 80 does not form a robust and durable hydrophobic film on the surface of the precursor droplets, thus avoiding the contradiction between conventional emulsification granulation methods and ionic crosslinking steps. As the droplets are about to completely cross the phase interface, the trace amount of Span 80 can also reduce the Laplace pressure on their tails, reduce tailing deformation, and help maintain gel sphericity.

[0018] Therefore, the present invention employs the above-mentioned ion crosslinking receiving bath for accelerating interfacial penetration, its preparation method, and its application, which have the following beneficial effects: (1) Significantly reduce the interfacial energy barrier and achieve direct droplet penetration and rapid cross-linking: This invention effectively removes dissolved gases in the solution by vacuum degassing the coagulation bath, and inhibits the hydrophobic aggregation phenomenon caused by microbubbles in the oil-water dispersion system, thereby forming a durable emulsion transition layer.

[0019] (2) Good biocompatibility and mild and safe process conditions: This invention abandons the forced release mode of traditional microfluidic methods that rely on metal chelators, oil phase acidification or organic reagents such as DMC. Interface control can be achieved simply by physical degassing coupled with extremely low concentration emulsifiers. The entire crosslinking process is completed under neutral and mild conditions, with no toxic or harmful reagent residues, which greatly improves the safety of the manufacturing process and the applicability of the product in the fields of biomedicine and food.

[0020] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0021] Figure 1 This is a mechanism diagram of an ion crosslinking receiving bath for accelerating interfacial penetration, its preparation method, and its application in Example 1 and Comparative Example 1 of the present invention. Figure 1 (a) is the mechanism diagram of Comparative Example 1. Figure 1 (b) is a mechanism diagram of Example 1; Figure 2 These are physical effect diagrams of the ion crosslinking receiving bath for accelerating interfacial penetration, its preparation method, and application examples 1 and 1 and 9 of this invention. Figure 2 (a) is a physical rendering of Comparative Example 1. Figure 2 (b) is a physical rendering of Example 1. Figure 2 (c) is a physical rendering of Comparative Example 9. Detailed Implementation

[0022] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims and are all within the protection scope of the present invention.

[0023] In this document, the term "embodiment" means that a specific feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The term "embodiment" appearing in various places throughout the specification does not necessarily refer to the same embodiment, nor does it specifically limit its independence or connection with other embodiments. In principle, in this application, as long as there are no technical contradictions or conflicts, the technical features mentioned in each embodiment can be combined in any way to form corresponding implementable technical solutions.

[0024] Unless otherwise defined, the technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains; the use of related terms herein is merely for the purpose of describing particular embodiments and is not intended to limit this application.

[0025] Fish oil (Ron, RH622156), medium-chain fatty acids (Langsifu, LSF0112), isopropyl myristate (Aladdin, T111830), CaCl2 (Aladdin, C399250), Span 80 (MERDA, M026823), ABS-like transparent engineering resin (Jinchao, MD5100), Brilliant Blue food coloring (Xinhengyan, AP016921).

[0026] The pectin was food-grade apple peel pectin with an esterification degree of 30±3%, purchased from Yantai Andre Pectin Co., Ltd. (galacturonic acid ≥65.0%, Shandong, China).

[0027] In this invention, unless otherwise specified, all other test materials and instruments are conventional test materials in the field and can be purchased through commercial channels.

[0028] Example 1 This embodiment provides a method for preparing an ion crosslinking receiving bath that accelerates interfacial penetration, comprising the following steps: S1. Preparation of separation bath: Dissolve Span 80 in fresh fish oil to a final concentration of 0.05% (v / v) to prepare the separation bath.

[0029] S2. Preparation of coagulation bath: Prepare a 2.5% (w / v) CaCl2 aqueous solution, place it in a vacuum device, and degas it under a vacuum pressure of 30 kPa for 30 min until the solution no longer produces new bubbles, thus obtaining a coagulation bath.

[0030] S3. Preparation of degassed emulsion receiving bath: Mix the separation bath and coagulation bath at a volume ratio of 3:1, emulsify using an ultrasonic disruptor with a working power of 300W, run for 2 seconds, pause for 1 second, and work for 1 minute to obtain the degassed emulsion receiving bath.

[0031] Example 2 The only difference between this embodiment and Example 1 is that, when preparing the separation bath, Span 80 was dissolved in fresh fish oil at a final concentration of 0.2% (v / v), while all other conditions were the same.

[0032] Comparative Example 1 The only difference between this comparative example and Example 1 is that no degassing treatment was performed when preparing the coagulation bath; all other conditions were the same.

[0033] Comparative Example 2 The only difference between this comparative example and Example 1 is that fresh fish oil was replaced with medium-chain fatty acids; all other conditions are the same.

[0034] Comparative Example 3 The only difference between this comparative example and Example 1 is that the separation bath preparation process is as follows: Span80 is dissolved in medium-chain fatty acids at a final concentration of 0.2% (v / v) to serve as the separation bath, and all other conditions are the same.

[0035] Comparative Example 4 The only difference between this comparative example and Example 1 is that the operation for preparing the separation bath is as follows: Span80 is dissolved in isopropyl myristate at a final concentration of 1% (v / v) as the separation bath, and all other conditions are the same.

[0036] Comparative Example 5 The only difference between this comparative example and Example 1 is that Span 80 was not added when preparing the separation bath; all other conditions were the same.

[0037] Comparative Example 6 The only difference between this comparative example and comparative example 5 is that fish oil was replaced with medium-chain fatty acids when preparing the separation bath; all other conditions were the same.

[0038] Comparative Example 7 The only difference between this comparative example and comparative example 5 is that fish oil was replaced with isopropyl myristate when preparing the separation bath; all other conditions were the same.

[0039] Comparative Example 8 The only difference between this comparative example and Example 2 is that fish oil was replaced with isopropyl myristate when preparing the separation bath; all other conditions were the same.

[0040] Comparative Example 9 The only difference between this comparative example and Example 1 is that Span 80 was dissolved in fresh fish oil at a final concentration of 1% (v / v) when preparing the separation bath; all other conditions were the same.

[0041] Comparative Example 10 The only difference between this comparative example and comparative example 9 is that fish oil was replaced with medium-chain fatty acids when preparing the separation bath; all other conditions were the same.

[0042] The receiving baths prepared in Example 1 and Comparative Examples 1-10 were used for the continuous manufacture of gel spheres, as follows: Mix 0.01% (w / v) Brilliant Blue food coloring with 3% (w / v) pectin at a ratio of 1:10, load the mixture into a 5mL syringe, and fix the syringe to a ZS3T-V3 syringe pump (Zibo Guanjie Electronic Technology Co., Ltd.). The pump speed is 9.5-131.0μL / min.

[0043] The vertical reciprocating linkage mechanism is manufactured using ABS-like transparent engineering resin and a Sonic Mini 8K S photopolymer 3D printer, driven by a 17HS4401S two-phase stepper motor (Shenzhen Yousheng Guangcai Electronics Co., Ltd.), with a motion frequency of 30-158rpm.

[0044] A receiving pool was fabricated using ABS-like transparent engineering resin and a Sonic Mini 8K S photopolymerization 3D printer to hold the receiving baths prepared in Example 1 and Comparative Examples 1-2. A syringe was connected to a needle via a latex tube, and the needle was fixed above different types of receiving pools. After droplets formed, their trajectory above the oil-water interface of the receiving bath was observed, and their penetration time was recorded. The results are shown in Table 1.

[0045] Table 1. Average penetration time of Examples 1-2 and Comparative Examples 1-10

[0046] "-" indicates that a large number of droplets remain suspended in the upper layer of the phase interface for more than 30 seconds without falling.

[0047] As shown in Table 1, the only difference between Comparative Example 1 and Example 1 is that the coagulation bath was not degassed. As a result, a large number of droplets in Comparative Example 1 were suspended at the phase interface for more than 30 seconds and could not fall, while the penetration time of Example 1 was only 0.7 seconds. This shows that even if the oil phase and the emulsifier composition are exactly the same, the droplets cannot overcome the interfacial energy barrier by their own weight without degassing. Vacuum degassing, by removing dissolved gases and inhibiting hydrophobic aggregation caused by microbubbles, is the core physical prerequisite for forming a durable emulsion transition layer and making interfacial penetration possible.

[0048] In Comparative Examples 5-7, regardless of whether fish oil, medium-chain fatty acids, or isopropyl myristate was used as the oil phase, the droplets were completely unable to penetrate without the addition of Span 80. This indicates that the oil-water interfacial tension is too high in the absence of emulsifier, preventing the droplets from overcoming the interfacial energy barrier. However, a higher emulsifier concentration is not always better. The penetration time in Example 1 was 0.7 s, in Example 2 it was extended to 2.8 s, and in Comparative Example 10 it was further extended to 7.3 s. The penetration time showed a monotonically increasing trend with increasing Span 80 concentration. This indicates that excessive emulsifier forms a dense hydrophobic adsorption film on the droplet surface, which becomes an additional energy barrier hindering the local oil film from evacuating and interfacial penetration. Overall, 0.05% Span 80 is the optimal concentration in this system.

[0049] At a Span 80 concentration of 0.05%, fish oil significantly outperformed medium-chain fatty acids and isopropyl myristate; at a Span 80 concentration of 0.2%, fish oil also outperformed medium-chain fatty acids and isopropyl myristate. This indicates that the molecular polarity and viscosity of fish oil form an optimal interfacial match with the degassed CaCl2 coagulation bath and Span 80 in this technical solution, minimizing the penetration energy barrier.

[0050] In Comparative Example 10, when medium-chain fatty acids were used as the oil phase in combination with 1% Span 80, the droplets could not penetrate at all. However, in Comparative Example 9, when fish oil was used as the oil phase in combination with the same concentration of 1% Span 80, although the penetration time was extended to 7.3 s, penetration was still achieved. This indicates that when a high concentration of emulsifier is combined with an oil phase whose molecular structure is incompatible, a supersaturated adsorption layer may be formed at the oil-water interface, or even interfacial gelation may be induced, causing the penetration barrier to rise sharply to the point of complete blockage.

[0051] The mechanisms of Example 1 and Comparative Example 1 are as follows: Figure 1 As shown, by Figure 1 As shown in (a), the oil-water interfacial tension in a conventional receiving bath is very high, which is sufficient to support the suspension of droplets with a diameter of 2500 μm (weight 82.6 μN), preventing them from quickly entering the lower aqueous phase.

[0052] Depend on Figure 1As shown in (b), the degassed emulsifying receiving bath increases the probability of microspheres coming into contact with the aqueous phase coagulation bath during their descent and embedding into the phase interface, resulting in the localization of the oil film on the surface, thus facilitating the successful completion of ionic cross-linking.

[0053] The physical effects of Example 1, Comparative Example 1, and Comparative Example 9 are as follows: Figure 2 As shown, by Figure 2 As shown in (a), the pectin droplets prepared in Comparative Example 1 were unable to penetrate the phase interface by their own weight and merge above the phase interface. Furthermore, in the initial state, small droplets in Comparative Example 1 were suspended above the rigid phase interface. As time went on, multiple droplets merged with each other, and the resulting large droplets still had difficulty penetrating the phase interface, ultimately affecting the monodispersity of the particles.

[0054] Depend on Figure 2 As shown in (b), the droplets in Example 1 exhibited minimal velocity changes during sedimentation, enabling them to directly penetrate the phase interface and enter the lower coagulation bath. Furthermore, the small droplets in Example 1 could smoothly pass through the flexible, diffuse phase interface. After entering the coagulation bath, the precursor rapidly released the brilliant blue dye, and the droplets maintained similar motion states from 0s to 15s, consistently exhibiting stable phase interface penetration behavior.

[0055] Depend on Figure 2 As shown in (c), the high concentration of emulsifier in Comparative Example 9 forms a dense hydrophobic film on the droplet surface. Although this solves the problem of droplet fusion, it makes it difficult for the droplets to penetrate the phase interface. Furthermore, the small droplets in Comparative Example 9 are affected by 1% Span 80, and the interface penetration time is significantly prolonged, with the number of retained droplets increasing continuously within 15 seconds.

[0056] As described above, vacuum degassing and low-concentration emulsifiers are two indispensable and synergistic conditions for pectin droplets to rapidly penetrate the oil-water interface and complete ionic cross-linking. On the one hand, Comparative Example 1 shows that if the coagulation bath is not degassed under vacuum, even with the addition of 0.05% Span 80, the oil-water interfacial tension is still extremely high (enough to support a weight of 82.6 μN), causing the droplets to be firmly blocked above the phase interface and to merge. This confirms that vacuum degassed is the decisive prerequisite for breaking the interfacial energy barrier and enabling the droplets to penetrate the phase interface directly by their own weight (the mechanism is to remove dissolved gas to suppress hydrophobic aggregation caused by microbubbles, thereby maintaining a durable emulsion transition layer).

[0057] On the other hand, Comparative Example 9 shows that although increasing the Span 80 concentration to 1% effectively prevents droplet fusion, excessive emulsifier forms a dense hydrophobic film on the droplet surface, which severely hinders its penetration into the phase interface. This indicates that there is a strict threshold effect in emulsifier concentration: only a low concentration of 0.05% is just right, which can moderately reduce interfacial tension and avoid tailing, without forming a strong barrier that hinders the drainage of local oil films. Only by combining a fully degassed CaCl2 coagulation bath with a 0.05% low-concentration Span 80 fish oil separation bath in Example 1 can the droplets obtain the probability of local contact with the aqueous phase during the sedimentation and embedding process, enabling the rapid drainage of the surface oil film and smooth entry into the lower aqueous phase to complete cross-linking. This provides a reliable guarantee for the mild and continuous manufacturing of monodisperse gel spheres.

[0058] Therefore, the present invention employs the above-mentioned ion crosslinking receiving bath for accelerating interface penetration, its preparation method and application. By performing vacuum degassing treatment on the coagulation bath, the hydrophobic aggregation phenomenon caused by microbubbles in the oil-water system is effectively suppressed, forming a durable emulsion transition layer. This significantly reduces the energy barrier at the oil-water interface, allowing droplets to directly penetrate the phase interface by their own weight and enter the lower aqueous phase to complete crosslinking, thus completely overcoming the defects of droplet suspension and fusion in conventional receiving baths.

[0059] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing an ion crosslinking receiving bath that accelerates interfacial penetration, characterized in that: Includes the following steps: S1. Preparation of separation bath: Dissolve Span 80 in fresh fish oil to prepare a separation bath. The volume concentration of Span 80 in fresh fish oil is 0.01-0.2%, and the amount of fresh fish oil used is 5-15 mL. S2. Preparation of coagulation bath: Prepare CaCl2 aqueous solution and degas under vacuum to obtain coagulation bath; S3. Preparation of degassing emulsification receiving bath: Mix the separation bath and the coagulation bath, and then emulsify the mixture to obtain the degassing emulsification receiving bath, i.e., the ion crosslinking receiving bath.

2. The method for preparing an ion crosslinking receiving bath to accelerate interfacial penetration according to claim 1, characterized in that: In S1, the volume concentration of Span 80 in fresh fish oil is 0.05%.

3. The method for preparing an ion crosslinking receiving bath to accelerate interfacial penetration according to claim 1, characterized in that: In S2, the mass-volume percentage of the CaCl2 aqueous solution is 2.5%, and the amount used is 20-40 mL.

4. The method for preparing an ion crosslinking receiving bath to accelerate interfacial penetration according to claim 1, characterized in that: In S2, the parameters for vacuum degassing are: vacuum pressure of 10-50 kPa and degassing time of 10-60 min, until no new bubbles are generated in the solution.

5. The method for preparing an ion crosslinking receiving bath to accelerate interfacial penetration according to claim 4, characterized in that: In S2, the vacuum pressure is 30 kPa and the degassing time is 30 min.

6. The method for preparing an ion crosslinking receiving bath to accelerate interfacial penetration according to claim 1, characterized in that: In S3, the volume ratio of the separation bath to the coagulation bath is (2-4):

1. Emulsification is performed using an ultrasonic disruptor with the following parameters: working power 300W, running time 2s, pause time 1s, and working time 1min.

7. An ion crosslinking receiving bath for accelerating interfacial penetration, characterized in that: It was prepared using the method described in any one of claims 1-6 for preparing an ion crosslinking receiving bath that accelerates interfacial penetration.

8. An application of an ion crosslinking receiving bath to accelerate interfacial penetration, characterized in that: The ion crosslinking receiving bath of claim 7, which accelerates interfacial penetration, is applied to the continuous manufacturing of gel spheres.

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