1. Introduction

Drug Delivery Systems (DDS) is the core direction of modern pharmacy, aiming to achieve precise control of drugsRelease rate, targeting, bioavailability, and stabilityEnhance treatment efficacy and reduce low toxicity and side effects. Traditional drug delivery methods, such as oral tablets and intravenous solutions, often face challengesLow solubility, poor targeting, significant burst release effect, low cellular uptake efficiencyIn the fields of nanomedicine (such as liposomes, polymer nanoparticles, mRNA vaccine carriers), formulations (such as sustained-release implants, inhaled dry powders), and biomacromolecule drugs (such as antibodies, gene therapy carriers), there is an urgent need for more advanced preparation techniques to achieve drug carriers with uniform particle size, high encapsulation efficiency, and stable structure.

　　Micro jet homogenizer（Microfluidic Homogenizer） ​As a method based onHigh pressure microjet and strong shear/collision effectsNanotechnology and homogenization equipment for drugs involves spraying drug solutions or suspensions into microchannels at ultra-high pressures (usually 100-300 MPa) to form high-speed jets, causing droplets or particles to undergo high-frequency shear, cavitation effects, and intense collisions between particles, thereby achievingParticle size refinement, uniform distribution, and controllable structure. Its unique ability to regulate microscale fluid dynamics has demonstrated irreplaceable advantages in the preparation and optimization of drug delivery systems, making it one of the key technologies driving the industrialization of drug formulations.

2、 The core working principle and technical characteristics of microjet homogenizer

（1） Basic working principle

The core of a microjet homogenizer is throughMulti physics field effects generated by high-pressure microjetThe refinement and homogenization of drug particles or droplets can be achieved through cutting, cavitation, and collision, and the workflow can be divided into three key stages:

​High pressure conveying and premixingDrug raw materials (such as solid drug powders, lipid/polymer solutions, and mixtures of water and oil phases) are pressurized by a high-pressure pump (usually a plunger pump) to​100~300 MPa​(Some models can reach 400 MPa), forming high-pressure fluid; For systems that require emulsification or encapsulation (such as liposomes, nanoemulsions), the oil phase (such as lipophilic drugs+lipids) is initially mixed with the water phase (such as water-soluble drugs+surfactants) through a pre mixing device.

​Microchannel jet and interactionHigh pressure fluid passes throughFixed microchannels made of diamond or sapphire material (typical diameter 50~300 μ m), in order to​500~1500 m/s​The ultra high speed jet is sprayed into the interaction chamber (Z-shaped or Y-shaped collision chamber). During this process, the fluid undergoes the following multiple physical field interactions:

​Shear forceThe shear action between high-speed jet and cavity wall or another reverse jet (shear rate can reach 10 ⁶~10 ⁷ s ⁻¹) directly peels off large particles or droplets, forming smaller primary particles;

​Cavitation effectWhen the local pressure of the fluid drops sharply (below the cavitation threshold), a large number of microbubbles (size 1-100 μ m) are generated, which then collapse at high speed and release enormous energy (microjet), impacting surrounding particles or droplets, promoting their fragmentation and dispersion;

​Particle collisionTwo or more high-speed jets collide head-on in the interaction chamber (with a velocity difference of up to 1000 m/s), causing particles or droplets to undergo severe impact and friction through momentum transfer, further refining and homogenization.

​Particle size control and outputAfter multiple cycles of processing (usually 1-5 times), the particle size of drug particles or droplets gradually decreases and tends to stabilize, and finally outputsNarrow particle size distribution (PDI<0.2), high uniformityDrug delivery systems such as nanoparticles, liposomes, and microemulsions.

（2） Technical features and advantages

Compared with traditional drug preparation techniques such as high-pressure homogenizer, ultrasonic emulsification, and mechanical stirring, the core advantages of microjet homogenizer are reflected in:

dimension	Micro jet homogenizer	Traditional techniques (such as high-pressure homogenizer/ultrasound)
​Particle size control accuracy​	Particle size range of 50~1000 nm (can be precisely adjusted to below 100 nm), PDI (dispersion index)<0.1~0.2	The particle size distribution is wide (PDI often>0.3), and small particle sizes (<200 nm) are difficult to prepare stably
​Mechanism of action​	Multi physics field synergy (shear+cavitation+collision), no thermal effect (to avoid degradation of thermosensitive drugs)	Ultrasound is prone to heat generation (disrupting biological activity), while high-pressure homogenizers rely on a single shear force
​Applicable system​	Compatible with aqueous, oil, and mixed phases (such as liposomes, nanoemulsions, polymer nanoparticles), supporting thermosensitive/oxygen sensitive drugs	Ultrasonic has poor effect on high viscosity system, and high-pressure homogenizer is easy to break low viscosity lotion
​Scale potential​	Modular design (laboratory type → production type continuous flow), suitable for GMP industrial production	Ultrasonic equipment is difficult to amplify, and the continuous process of traditional homogenizers is complex
​Structural stability​	Retain drug activity (such as proteins, mRNA) through gentle action, reduce aggregation and denaturation	High energy ultrasound or vigorous stirring can easily lead to protein aggregation or liposome membrane rupture

3、 Typical application of microjet homogenizer in drug delivery system

（1） Nanoparticles and polymer carriers (such as PLGA nanoparticles, albumin nanoparticles)

​Application scenariosUsed for encapsulating small molecule chemotherapy drugs (such as paclitaxel, doxorubicin), proteins/peptides (such as insulin, vaccine antigens), or nucleic acids (such as siRNA), forming nano carriers through polymers (such as polylactic acid hydroxyacetic acid copolymer, PLGA) or natural polymers (such as human serum albumin, HSA), prolonging drug half-life and enhancing targeting.

​The function of microjet homogenizer​：

​Particle size refinementPolymer drug colostrum (usually with a particle size of 1-10 μ m) is refined to 100-300 nm (even<100 nm) through microjet treatment to improve blood circulation time (EPR effect, which refers to the high permeability and retention effect of tumor tissue);

​Uniform distributionReduce the particle size distribution width (PDI<0.15) to avoid sudden release effects caused by large particles (rapid drug release) or renal clearance of small particles;

​Encapsulation rate optimizationBy controlling pressure and cycle times, balance drug encapsulation efficiency (usually>80%) with carrier integrity (such as membrane structure stability of PLGA nanoparticles).

​Case StudyAfter treatment with a microjet homogenizer, the average particle size of paclitaxel PLGA nanoparticles decreased from 800 nm to 150 nm, the PDI decreased from 0.4 to 0.12, and the tumor enrichment increased threefold after tail vein injection in mice (compared to the untreated group).

（2） Liposomes and lipid like nanoparticles (such as mRNA vaccine carriers, doxorubicin liposomes)

​Application scenariosLiposomes are spherical vesicles formed by the encapsulation of a phospholipid bilayer around a water or oil core, widely used for delivering hydrophilic drugs (such as doxorubicin aqueous solution), hydrophobic drugs (such as paclitaxel dissolved in the lipid core), or nucleic acids (such as mRNA, siRNA). Lipid nanoparticles (such as LNP, lipid nanoparticles) are the core carriers of mRNA vaccines, forming stable membrane structures through cationic lipids and auxiliary lipids.

​The function of microjet homogenizer​：

​Preparation of Small Single Room LiposomesMixing phospholipids, cholesterol, and drugs in the aqueous/oil phase through high-speed micro jet collision to form uniformly sized closed liposomes (usually 50-200 nm), avoiding the multi chambered liposomes (uneven particle size) produced by traditional thin film dispersion methods;

​LNP structural stabilizationIn the preparation of mRNA LNP, a microjet homogenizer promotes the electrostatic recombination of cationic lipids and mRNA through mild shear force, while controlling the thickness of the lipid membrane (about 5-10 nm) to ensure mRNA encapsulation efficiency (>90%) and cell uptake efficiency;

​Aseptic and scalableBy designing a disposable tubing that is compatible with GMP, it meets the sterile production requirements of liposomal drugs (such as intravenous injection of doxorubicin liposomes).

​Case Study: The LNP carrier of COVID-19 mRNA vaccine was optimized by a micro fluidic homogenizer, and the particle size was stable at 80~100 nm (PDI<0.1), the mRNA encapsulation rate was>95%, and the immunogenicity after intramuscular injection was significantly higher than that of LNP prepared by traditional homogenization method.

（3） Nanoemulsions and microemulsions (such as cyclosporine eye emulsion, paclitaxel albumin microemulsion)

​Application scenariosNanoemulsions (particle size 100-500 nm) and microemulsions (particle size 10-100 nm) are thermodynamically stable systems spontaneously formed by oil phase, water phase, and surfactants, used for delivering insoluble drugs (such as cyclosporine and paclitaxel) or enhancing transdermal/mucosal absorption (such as ocular administration).

​The function of microjet homogenizer​：

​Particle size refinement and O/W/W type controlMixing the oil phase (such as paclitaxel dissolved in ethyl oleate) with the water phase (such as surfactant+buffer) through microjet to form a uniformly sized nanoemulsion (such as paclitaxel albumin microemulsion with a particle size reduced from 500 nm to 80 nm), enhancing drug solubility (such as increasing the solubility of cyclosporine by more than 100 times);

​Enhanced interface stabilityOptimize the arrangement density of surfactants at the oil-water interface through strong shear force, reduce droplet coalescence (improve storage stability, such as particle size change<5% after 6 months);

​Transdermal/mucosal optimizationSmall particle size nanoemulsion (<100 nm) can penetrate the cornea or skin stratum corneum (traditional emulsions with particle size>200 nm are difficult to penetrate), used for the treatment of eye inflammation or skin cancer.

​Case StudyAfter treatment with a microjet homogenizer, the particle size of cyclosporine nanoemulsion decreased from 300 nm to 50 nm, and the bioavailability of the drug increased fourfold after local administration to rabbit eyes (compared to ordinary emulsions).

（4） Solid lipid nanoparticles (SLN) and nanocrystals (such as insoluble API nanomaterialization)

​Application scenariosSLN is a nanoparticle (particle size 50-500 nm) that encapsulates drugs using solid lipids (such as stearic acid and triglycerides) as carriers, used to improve the solubility and dissolution rate of poorly soluble drugs (such as itraconazole and ibuprofen); Nanocrystals are directly prepared into nanoscale crystals (particle size<1000 nm) by physically crushing drug APIs (such as anti-tumor drugs), relying on the "nanoscale effect" to enhance bioavailability.

​The function of microjet homogenizer​：

​SLN particle size controlMix molten lipids with drugs and rapidly cool to form colostrum, which is then refined to 100-300 nm using a microjet homogenizer to avoid large particles (>500 nm) generated by traditional emulsification cooling methods;

​Surface modification of nanocrystalsAfter micro jet treatment, the nanocrystals (such as paclitaxel nanocrystals with a particle size reduced from 5 μ m to 200 nm) can be further coated with surfactants (such as polysorbate 80) to improve hydrophilicity and prolong blood circulation time (avoiding rapid clearance of the reticuloendothelial system).

​Case StudyAfter optimization with a microjet homogenizer, the particle size of itraconazole SLN remained stable at 200 nm. After oral administration to rats, the AUC (area under the drug time curve) increased by 6 times compared to the crude suspension.

4、 Application advantages and challenges of microjet homogenizer

（1） Summary of Core Advantages

​Uniformity and controllability of particle sizeBy precisely adjusting the pressure (100-300 MPa), cycle times (1-5 times), and microchannel structure, particle size customization within the range of 50-1000 nm can be achieved to meet the targeting requirements of different DDS (such as EPR effect<200 nm, intracellular delivery<100 nm);

​Multi system compatibilitySuitable for aqueous, oil, and mixed phases (such as liposomes and nanoemulsions), compatible with thermosensitive (such as proteins), oxygen sensitive (such as mRNA), and high viscosity drugs (such as polymer solutions);

​Structural stability protectionNon thermal processing (energy mainly comes from mechanical shearing, temperature increase<5 ℃) reduces biological activity loss (such as protein aggregation rate<5%, liposome membrane integrity>90%);

​Scale potentialThe laboratory type (processing capacity of 10-100 mL) and production type (continuous flow, processing capacity of 1-100 L/h) equipment are mature and meet GMP production requirements (such as reducing cross contamination of disposable pipelines).

（2） Current challenges and improvement directions

​Equipment cost and maintenanceMicro jet homogenizers (such as diamond interactive cavity materials) are expensive (in the millions of RMB), and diamond microchannels are prone to wear and tear (requiring regular replacement, with a cost of about thousands per time);

​Complexity of process parameter optimizationThe optimal pressure and cycle times of different drug systems (such as liposomes vs polymer nanoparticles) vary greatly, and need to be optimized through experimental design (such as DOE) system;

​Amplify the uniformity of productionWhen transitioning from laboratory trials to industrial continuous flow production, it is necessary to address the issues of uniformity of microchannel flow velocity distribution (to avoid local over treatment or under treatment) and inter batch reproducibility;

​Drug adaptabilityFor certain ultra-low solubility drugs (such as compounds with logP>6) or high concentration formulations (>200 mg/mL), it may be necessary to combine other techniques (such as high-pressure homogenization pretreatment or surfactant screening).

5、 Future Development Trends and Application Prospects

（1） Technology integration and innovation

​Microfluidics microfluidics combined with microfluidicsCombining precise fluid manipulation with microfluidic chips (such as droplet generation and laminar mixing) to further enhance the structural controllability of drug carriers (such as multilayer liposomes and core-shell nanoparticles);

​Online monitoring and feedback controlIntegrating dynamic light scattering (DLS), laser particle size analyzer, and other real-time monitoring of particle size distribution, and dynamically adjusting pressure and cycle times through AI algorithms to achieve "intelligent preparation";

​Green process developmentReduce the use of organic solvents (such as using water in oil in water (W/O/W) emulsification instead of organic phases), in compliance with environmental and safety requirements.

（2） Expansion of application areas

​Biopharmaceuticals and Gene TherapyLarge scale preparation of mRNA vaccines, CRISPR-Cas9 gene editing vectors, and CAR-T cell therapy adjuncts (such as nanodelivery activators);

​Personalized healthcareCustomized DDS tailored to patient specific needs (such as individualized liposome chemotherapy regimens for cancer patients);

​New administration routes: inhaled nano preparations (such as lung administration for asthma), transdermal nano patches (such as percutaneous delivery of diabetes insulin), oral nano capsules (such as insoluble drugs to improve bioavailability).

VI. Conclusion

Micro jet homogenizer passes throughMulti physics field synergy driven by high-pressure microjetThis provides core technical support for the homogenization of particle size, structural stability, and precise functionality of drug delivery systems. Its wide application in formulations such as nanoparticles, liposomes, nanoemulsions, and nanocrystals not only solves the problems of uncontrollable particle size, low encapsulation efficiency, and loss of biological activity in traditional preparation techniques, but also promotes the rapid development of biopharmaceuticals, gene therapy, and personalized medicine. In the future, with the reduction of equipment costs, the improvement of process intelligence, and the integration with other technologies, micro jet homogenizers will play a more critical role in the field of drug delivery and become the "core engine" of formulation industrialization.