Ultrasonic Treatment of Nanoparticles for Pharmaceuticals

Probe-type sonicators play a crucial role in pharmaceutical research and manufacturing by providing a powerful and controlled means of achieving particle size reduction, cell disruption, and homogenization. Sonicators utilize ultrasonic waves to generate cavitation, resulting in the formation and collapse of microscopic bubbles. This phenomenon generates intense shear forces and shock waves, effectively breaking down particles or disrupting cells.

Here are some key aspects of the use of probe-type sonicators in pharmaceutical applications:

  • تقليل حجم الجسيمات: Probe sonicators are employed to reduce the particle size of active pharmaceutical ingredients (APIs) or other compounds. A small and uniform size of particles is vital for enhancing bioavailability, dissolution rates, and overall efficacy of pharmaceutical formulations.
  • Cell Disruption: In biopharmaceutical research, probe sonicators are utilized for cell disruption to release intracellular components. This is particularly important for the extraction of proteins, enzymes, and other biomolecules from microbial cells or cultured mammalian cells.
  • التجانس: Homogenization of pharmaceutical formulations is essential for ensuring uniform distribution of ingredients. Probe sonicators aid in achieving homogeneity by breaking down agglomerates and dispersing components evenly.
  • Nanoemulsion and Liposome Formation: Sonication is used to create stable nanoemulsions and liposomes in pharmaceutical formulations. These nanoscale delivery systems are employed for drug delivery to enhance solubility and bioavailability.
  • Quality Control and Process Optimization: Sonication is a valuable tool for quality control in pharmaceutical manufacturing. It helps in optimizing processes by ensuring consistent particle size distribution and homogeneity, contributing to batch-to-batch reproducibility.
  • صياغة الدواء وتطويره: During drug formulation and development, probe sonicators are utilized to prepare stable suspensions, emulsions, or dispersions. This is critical for designing pharmaceutical products with desired physical and chemical properties.

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Ultrasonically agitated reactor for improved peptide synthesis.

Ultrasonically agitated reactor for improved and accelerated synthesis. The picture shows the ultrasonicator UP200St in a stirred glass reactor.

Nanomaterials in Pharmaceuticals

Ultrasonic technologies play a pivotal role in the preparation, processing, and functionalization of nanomaterials in pharmaceutical research and manufacturing. The intense effects of high-power ultrasound, including acoustic cavitation, contribute to breaking agglomerates, dispersing particles, and emulsifying nano-droplets. Hielscher high-performance sonicators provide a reliable and efficient solution for pharmaceutical standards, ensuring safe production and facilitating scale-up without additional optimization efforts.

Processing Nanomaterials

Nanomaterials, particularly nanoparticles, have revolutionized drug delivery in pharmaceuticals, offering a proven method for administering active agents orally or through injection. This technology enhances the efficiency of drug dosing and delivery, opening novel avenues for medical treatments. The ability to deliver drugs, heat, or other active substances directly to specific cells, particularly diseased cells, marks a significant advancement.

In cancer therapy, nano-formulated drugs have demonstrated promising results, leveraging the advantage of nano-sized particles to deliver high drug doses directly to tumor cells, maximizing therapeutic effects while minimizing side effects on other organs. The nanoscale size allows these particles to pass through cell walls and membranes, releasing active agents precisely at targeted cells.

Processing nanomaterials, defined as particles with dimensions less than 100nm, presents challenges that demand higher efforts. Ultrasonic cavitation emerges as a well-established technology for deagglomerating and dispersing nanomaterials. Carbon Nanotubes (CNTs), especially Multi-Walled Carbon Nanotubes (MWCNTs) and Single-Walled Carbon Nanotubes (SWCNTs), showcase unique properties, offering a large inner volume for encapsulating drug molecules and distinct surfaces for functionalization.
 

Sonochemically prepared single-walled carbon nanotubes (SWNTs/ SWCNTs)

Sonochemical production of SWCNTs. Silica powder in a solution of ferrocene-xylene mixture has been sonicated for 20 min. at room temperature and under ambient pressure. Sonication produces high-purity SWCNTS on the surface of the silica powder. (Jeong et al. 2004)

 

Functionalized Carbon Nanotubes (f-CNTs) play a crucial role in enhancing solubility, allowing efficient tumor targeting, and avoiding cytotoxicity. Ultrasonic techniques facilitate their production and functionalization, such as the sonochemical method for high-purity SWCNTs. Moreover, f-CNTs can serve as vaccine delivery systems, linking antigens to carbon nanotubes to induce specific antibody responses.
Ceramic nanoparticles derived from silica, titania, or alumina present porous surfaces, making them ideal drug carriers. Ultrasonic synthesis and precipitation of nanoparticles, utilizing sonochemistry, provide a bottom-up approach for preparing nanosize compounds. The process enhances mass transfer, resulting in smaller particle sizes and higher uniformity

Ultrasonic Synthesis and Precipitation of Nanoparticles

Ultrasonication plays a vital role in functionalizing nanoparticles. The technique efficiently breaks up boundary layers around particles, allowing new functional groups to reach the particle surface. For instance, ultrasonic functionalization of Single-Walled Carbon Nanotubes (SWCNTs) with PL-PEG fragments interferes with nonspecific cell uptake while promoting specific cellular uptake for targeted applications.

Ultrasonic homogenizers allow for an effective dispersing, deagglomeration and mfunctionalization of nano materials.

Hielscher lab sonicator UP50H for the sonication of small volumes, e.g. dispersing MWNTs.

To obtain nanoparticles with specific characteristics and functions, the surface of the particles has to been modified. Various nanosystems like polymeric nanoparticles, liposomes, dendrimers, carbon nanotubes, quantum dots etc. can be successfully functionalized for efficient use in pharmaceutics.

Practical Example of Ultrasonic Particle Fuctionalization:

Ultrasonic Functionalization of SWCNTs by PL-PEG: Zeineldin et al. (2009) demonstrated that the dispersion of single walled carbon nanotubes (SWNTs) by ultrasonication with phospholipid-polyethylene glycol (PL-PEG) fragments it, thereby interfering with its ability to block nonspecific uptake by cells. However, unfragmented PL-PEG promotes specific cellular uptake of targeted SWNTs to two distinct classes of receptors expressed by cancer cells. Ultrasonic treatment in the presence of PL-PEG is a common method used to disperse or functionalize carbon nanotubes and the integrity of PEG is important to promoting specific cellular uptake of ligand-functionalized nanotubes. Since fragmentation is a likely consequence of ultrasonication, a technique commonly used to disperse SWNTs, this maybe a concern for certain applications such as drug delivery.
 

Sonication is a highly effective method to modify and functionalize nanoparticles

Ultrasonic dispersion of SWCNTs with PL-PEG (Zeineldin et al., 2009)

 

Ultrasonic Liposome Formation

Another successful application of ultrasound is the preparation of liposomes and nano-liposomes. Liposome-based drug and gene delivery systems play a significant role in manifold therapies, but also in cosmetics and nutrition. Liposomes are good carriers, as water soluble active agents can be placed into the liposomes aqueous center or, if the agent is fat soluble, in the lipid layer. Liposomes can be formed by the use of ultrasonics. The basic material for liposome preparation are amphilic molecules derived or based on biological membrane lipids. For the formation of small unilamellar vesicles (SUV), the lipid dispersion is sonicated gentlye.g. with the handheld ultrasonicator UP50H (50W, 30kHz), the VialTweeter or ultrasonic cup-horn . The duration of such an ultrasonic treatment lasts approx. 5 – 15 minutes. Another method to produce small unilamellar vesicles is the sonication of the multi-lamellar vesicles liposomes.
Dinu-Pirvu et al. (2010) reports the obtaining of transferosomes by sonicating MLVs at room temperature.
Hielscher Ultrasonics offers various ultrasonic devices, sonotrodes and accessories to meet the requirement of all kinds of processes.
Read more about ultrasonically-extracted and encapsulated Aloe vera extract!

Ultrasonic Encapsulation of Agents into Liposomes

Liposomes works as carriers for active agents. Ultrasound is an effective tool to prepare and form the liposomes for the entrapment of active agents. Before encapsulation, the liposomes tend to form clusters due to the surface charge-charge interaction of phospholipid polar heads (Míckova et al. 2008), furthermore they have to be opened. By way of example, Zhu et al. (2003) describe the encapsulation of biotin powder in liposomes by ultrasonication. As the biotin powder was added into the vesicle suspension solution, the solution has been sonicated for approx. 1 hour. After this treatment, biotin was entrapped in the liposomes.

Liposomal Emulsions

To enhance the nurturing effect of moisturizing or anti-aging cremes, lotions, gels and other cosmeceutical formulations, emulsifier are added to the liposomal dispersions to stabilize higher amounts of lipids. But investigations had shown that the capability of liposomes is generally limited. With the addition of emulsifiers, this effect will appear earlier and the additional emulsifiers cause a weakening on the barrier affinity of phosphatidylcholine. Nanoparticlescomposed of phosphatidylcholine and lipids – are the answer to this problem. These nanoparticles are formed by an oil droplet which is covered by a monolayer of phosphatidylcholine. The use of nanoparticles allows formulations which are capable to absorb more lipids and remain stable, so that additional emulsifiers are not needed.
Ultrasonication is a proven method for the production of nanoemulsions and nanodispersions. Highly intensive ultrasound supplies the power needed to disperse a liquid phase (dispersed phase) in small droplets in a second phase (continuous phase). In the dispersing zone, imploding cavitation bubbles cause intensive shock waves in the surrounding liquid and result in the formation of liquid jets of high liquid velocity. In order to stabilize the newly formed droplets of the disperse phase against coalescence, emulsifiers (surface active substances, surfactants) and stabilizers are added to the emulsion. As coalescence of the droplets after disruption influences the final droplet size distribution, efficiently stabilizing emulsifiers are used to maintain the final droplet size distribution at a level that is equal to the distribution immediately after the droplet disruption in the ultrasonic dispersing zone.

Liposomal Dispersions

Liposomal dispersions, which are based on unsaturated phosphatidylchlorine, lack in stability against oxidation. The stabilization of the dispersion can be achieved by antioxidants, such as by a complex of vitamins C and E.
Ortan et al. (2002) achieved in their study concerning the ultrasonic preparation of Anethum graveolens essential oil in liposomes good results. After sonication, the dimension of liposomes were between 70-150 nm, and for MLV between 230-475 nm; these values were approximately constant also after 2 month, but inceased after 12 month, especially in SUV dispersion (see histograms below). The stability measurement, concerning essential oil loss and size distribution, also showed that liposomal dispersions maintained the content of volatile oil. This suggests that the entrapment of the essential oil in liposomes increased the oil stability.
 

Ultrasonically prepared multi-lamellar vesicles (MLV) and single uni-lamellar vesicles (SUV) show a good stability concerning the essential oil loss and the particle size distribution.

Stability of MLV and SUV dispersions after 1 year. Liposomal formulations were stored at 4±1 ºC.
(Study and graphic: ©Ortan et al., 2009):

 
Click here to read more about the ultrasonic liposome preparation!

High-Performance Sonicators for Pharmaceutical Research and Manufacturing

Hielscher Ultrasonics is your top supplier of high-quality, high-performance sonicators for research and manufacturing of pharmaceuticals. Devices in the range from 50 watts up to 16,000 watts allow to find the right ultrasonic processor for every volume and every process. By their high performance, reliability, robustness and easy operation, the ultrasonic treatment is an essential technique for the preparation and processing of nanomaterials. Equipped with CIP (clean-in-place) and SIP (sterilize-in-place), Hielscher sonicators guarantee safe and efficient production according to pharmaceutical standards. All specific ultrasonic processes can be easily tested in lab or bench-top scale. The results of these trials are completely reproducible, so that the following scale-up is linearly and can be easily made without additional efforts regarding the process optimization.

لماذا Hielscher الموجات فوق الصوتية؟

  • high efficiency
  • أحدث التقنيات
  • موثوقيه & متانه
  • تحكم دقيق وقابل للتعديل في العملية
  • batch & مضمنه
  • for any volume
  • برنامج ذكي
  • الميزات الذكية (على سبيل المثال ، قابلة للبرمجة ، وبروتوكول البيانات ، والتحكم عن بعد)
  • سهل وآمن للعمل
  • صيانة منخفضة
  • التنظيف المكاني (التنظيف المكاني)

Hielscher Sonicators: Design, Manufacturing and Consulting – جودة صنع في ألمانيا

Hielscher الموجات فوق الصوتية معروفة جيدا لأعلى معايير الجودة والتصميم. المتانة والتشغيل السهل تسمح بالتكامل السلس للموجات فوق الصوتية لدينا في المنشآت الصناعية. يتم التعامل بسهولة مع الظروف القاسية والبيئات الصعبة بواسطة الموجات فوق الصوتية Hielscher.

Hielscher Ultrasonics هي شركة حاصلة على شهادة الأيزو وتركز بشكل خاص على الموجات فوق الصوتية عالية الأداء التي تتميز بأحدث التقنيات وسهولة الاستخدام. بطبيعة الحال، الموجات فوق الصوتية Hielscher هي CE المتوافقة وتلبية متطلبات UL، وكالة الفضاء الكندية وبنفايات.

The table below gives you an indication of the approximate processing capacity of our ultrasonicators:

Batch VolumeFlow RateRecommended Devices
0.5 to 1.5mLn.a.VialTweeter
1 to 500mL10 to 200mL/minUP100H
10 to 2000mL20 to 400mL/minUP200Ht, UP400St
0.1 to 20L0.2 to 4L/minUIP2000hdT
10 to 100L2 to 10L/minUIP4000hdT
15 إلى 150 لتر3 إلى 15 لتر / دقيقةUIP6000hdT
n.a.10 to 100L/minUIP16000
n.a.largercluster of UIP16000

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Ultrasonic extraction setup: Probe-type ultrasonicator UIP2000hdT (2000 watts) in a pharma-grade stainless steel reactor.

Ultrasonic process setup: Probe-type ultrasonicator UIP2000hdT (2000 watts) in a pharma-grade stainless steel reactor.



Literature/References

     

    Ultrasound is an innovative technology that is used successfully for sonochemical synthesis, deagglomeration, dispersion, emulsification, functionalization and activation of particles. Particularly in nanotechnology, ultrasonication is an essential technique for the synthesis and processing purposes of nano-size materials. Since nanotechnology has gained this outstanding scientific interest, nano-sized particles are utilized in extraordinarily many scientific and industrial fields. The pharmaceutical industry has discovered the high potential of this flexible and variable material, too. Consequently, nanoparticles are involved into various functional applications in the pharmaceutical industry, these include:

    • drug delivery (carrier)
    • diagnostic products
    • product packaging
    • biomarker discovery
Ultrasonic high-shear homogenizers are used in lab, bench-top, pilot and industrial processing.

Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for mixing applications, dispersion, emulsification and extraction on lab, pilot and industrial scale.

We will be glad to discuss your process.

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