Hielscher Ultrasound Technology

Ultrasonic Nanostructuring of Antibiotics

Ultrasonically-assisted production of antibiotics can increase their effectiveness, eben against drug-resistant bacteria: The increasing number of antibiotic-resistant bacteria strains is a still unsolved problem making bacterial infections, which have been successfully treated with antibiotics within the last decades, a worldwide health threat again. Ultrasonic nano-structuring of antibiotics is a promising technique to increase the effectiveness of antibiotics such as tetracycline against drug-resistant bacteria.

Antibiotics and Antibiotic-Resistant Bacteria

Escherichia coli bacteria are reliably lysed using ultrasonic tissue homogenizers.Antibiotic resistance happens when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them. That means the germs are not killed and continue to grow. Infections caused by antibiotic-resistant germs are difficult, and sometimes impossible, to treat.
Antibiotic resistance of bacteria is attributed to the over-use as well as mis-use of antibiotic drugs. Overuse and misuse refer mainly to inappropriate prescriptions and extensive agricultural use
For common antibiotics such as penicilin, tetracycline, methicillin, erythromycin, gentamicin, vancomycin, imipemen, ceftazidime, levofloxacin, linezolid, daptomycin, and ceftraroline, certain bacteria strains have mutated and developed antibiotic resistance.
Main cause of the development of antibiotic-resistant bacteria lies in the overuse and misuse of antibiotic drugs. Every time a patient is administered antibiotics, sensitive bacteria are killed. However, if there are resistant bacteria, which are not eradicated by the drug treatment, they grow and multiply. Thereby, the repeated and inappropriate use of antibiotics cause the increase of drug-resistant bacteria.
Multi-Drug Resistant (MDR) bacteria are a serious health threat since they do not respond to common antibiotic treatment, which is supposed to kill the germs.
Among gram-positive pathogens, a global pandemic of resistant S. aureus (e.g., methicillin-resistant Staphylococcus aureus; MRSA) and Enterococcus species currently poses the biggest threat. Gram-negative pathogens such as Enterobacteriaceae (e.g., Klebsiella pneumoniae), Pseudomonas aeruginosa, and Acinetobacterare becoming resistant to nearly all the antibiotic drug options available.

Ultrasonic processor UIP1000hdT for the nano-structuring of antibiotics in order to increase their effectiveness against antibiotic-resistant bacteria strains.

UIP1000hdT – a 1kW powerful ultrasonic processor for the nano-structuring of antibiotics such as tetracycline to increase their effectiveness against antibiotic-resistant bacteria

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Ultrasonically Nano-Sized Antibiotics

Nano-sized pharmaceuticals are known to excel micron-sized drug molecules often due to increased absorption rates, higher bioavailability, and superior effectiveness. Antibiotics are widely used to treat bacterial infections. However, the rapid development of more and more drug-resistant bacteria strains makes the development of new or the modification of existing antibiotic drugs necessary. Reducing the particle size of antibiotics such as tetracycline via sonication is one easy, rapid and promising strategy to improve the effectiveness of antibiotics against non-resistant and resistant bacteria strains.

Ultrasonically NanoStructured Tetracycline

The UIP1000hdT can be used for beaker sonication as well as with flow cell reactor (Click to enlarge!)Kassirov et al. (2018) treated tetracycline ultrasonically to improve the drug’s effectiveness against pathogens. In their study, they used Escherichia coli Nova Blue TcR, a strain with antibiotic resistance, and E. coli 292–116 (without drug resistance). Tetracycline, a common broad-spectrum antibiotic, was modified using industrial ultrasonicator UIP1000hdT (Hielscher, Germany; see picture left). The research team found that the sonochemical treatment with the UIP1000hdT increases the effectiveness of antibacterial properties up to 25% against the resistant strain and up to 100% against the sensitive strain. Even a long-term storage of the nanostructured tetracycline at +4ºC does not reduce the antimicrobial properties.
The ultrasonic processing parameters such as amplitude, energy input, and sonication time were determined as critical factors that influence the change in antimicrobial properties against both sensitive and resistant cells.
The ultrasonic treatment results in a more uniform particle size distribution of nano-sized drug particles, which might lead to a higher bioavailability, bioaccessibility and thereby effectiveness of the tetracycline molecules.
The obtained data shows that sonochemical modification of antibiotics can be a new promising and cheap approach to the development of new drugs effective for antibiotic therapy against drug resistance strains.

Ultrasonic nanostructuring of the antibiotic drug tetracycline increases the effectiveness against drug-resistant bacteria.

Sonication of tetracycline with the UIP1000hdT.
A – FTIR spectra of “free” tetracycline; B – FTIR spectra of SN tetracycline after 5 min sonication; C – Size distribution histogram of “free” tetracycline; D – Size distribution histogram of SN tetracycline after 5 min sonication.
Study and figure by Kassirov et al. 2018.

Ultrasonic processor UIP2000hdT (2kW) with stirred batch reactor

Ultrasonic processor UIP2000hdT (2kW) with batch reactor

Advantages of Ultrasonic Nanostructured Drugs

Ultrasonication offers enormous possibilities for the synthesis of a broad spectrum of nanostructured materials and is used in many industries. Ultrasonic production of nano-sized pharmaceuticals such as antibiotics, anti-virals and other medicines is highly promising since these nano-sized drugs show often a significantly higher absorption rate, bioavailability and effectiveness. Therefore many enhanced drug formulations involve ultrasonication in order to nanostructure drug molecules, encapsulate drugs into nano-emulsions, nano-liposomes, niosomes, solid-lipid nanoparticles (SLNs), nano-structured lipid carries (NLCs), and other nano-sized inclusion complexes.

Ultrasonic Formulation of Nano-Sized Drugs

  • Ultrasonic Nano-Emulsions
  • Ultrasonic Liposomes
  • Ultrasonic Niosomes
  • Ultrasonic Solid-Lipid Nanoparticles (SLNs)
  • Ultrasonic Nanostructured Lipid Carriers (NLCs)
  • Ultrasonic Inclusion Complexation
  • Ultrasonically Doped and Functionalized Nanoparticles
  • Ultrasonic Vaccine Formulations
  • Ultrasonic Formulation of Intranasal Vaccine

Ultrasonic treatment of nanomaterials with antibacterial properties is also used to synthesize nano-structured materials (e.g. nano-silver, nano ZnO) and to apply them to textiles in order to manufacture antibacterial medical textiles and other functional fabrics. For instance, a single-step ultrasonic process is used to fabricate durable coatings of cotton fabrics with antibacterial ZnO nanoparticles.

The Advantage of Ultrasonic Synthesis of Nano-Sized Drugs

  • High performance particle size reduction
  • Exact control over process parameters
  • Fast Process
  • Non-thermal, precise temp control
  • Linear Scalability
  • Reproducibility
  • Process standardisation / GMP
  • Autoclavable probes and reactors
  • CIP / SIP
  • Exact control over particle size and encapsulation
  • High drug loading of active substances

How Does Ultrasonic Synthesis of Nano-Structured Materials Work?

Ultrasonication and sonochemistry, which is the application of high-power ultrasound to chemical systems, are used widely to produce high-quality nano-sized materials (e.g., nanoparticles, nano-emulsions). Sonication and sonochemistry enable for or facilitate the production of high-performance nano-sized materials. The advantage of ultrasonic synthesis of nano-particles is the simplicity and effectiveness. Whilst alternative production methods of nano-structured materials require high bulk temperatures, pressures, and / or long reaction times, ultrasonic synthesis often allows for a facile, rapid and efficient production of nanomaterials. Both, sonochemical and sonomechanical effects generated by high-intensity ultrasonics are responsible for the synthesis or functionalization/modification of nano-sized particles. Coupling high-power ultrasonic waves into liquids results in acoustic cavitation: the formation, growth, and implosive collapse of bubbles, and can be categorized as primary sonochemistry (gas-phase chemistry occurring inside collapsing bubbles), secondary sonochemistry (solution-phase chemistry occurring outside the bubbles), and sonomechanical / physical modifications (caused by high-speed liquid jets, shockwaves, and/or inter-particle collisions in slurries). (cf. Hinman and Suslick, 2017) The cavitational impact on particles results in size reduction, nano-structuring (nano-dispersion, nano-emulsification), as well as in particle functionalization and modification.
Read more about ultrasonic milling and dispersing of particles!

Ultrasonic Nanostructuring of Particles

Ultrasonic Probes for the Synthesis of Nano-Structured Pharmaceuticals

Hielscher Ultrasonic is long-time experienced in the design, manufacturing, distribution and service of high-performance ultrasonic homogenisers for the pharmaceutical and food industry.
The preparation of high-quality nano-sized drug particles, liposomes, solid lipid nanoparticles, polymeric nanoparticles, cyclodextrin complexes, and vaccines are processes, in which Hielscher ultrasonic systems are widely used and are valued for their high reliability and superior quality output. Hielscher ultrasonicators allow for precise control over all process parameters, such as amplitude, temperature, pressure and sonication energy. The intelligent software automatically protocols all sonication parameters (time, date, amplitude, net energy, total energy, temperature, pressure) on the built-in SD-card. This facilitates process and quality control significantly and helps to fulfil Good Manufacturing Practices (GMP).

Ultrasonic Mixers for Every Product Capacity

Precise control over the ultrasonic process parameters by Hielscher Ultrasonics' intelligent softwareHielscher Ultrasonics product range covers the full spectrum of ultrasonic processors from compact lab ultrasonicators over bench-top and pilot systems to fully-industrial ultrasonic processors with the capacity to process truckloads per hour. The full product range allows us to offer you the most suitable ultrasonic shear mixer for your process capacity and goals. This allows you to develop and test your application in small lab size and scale it then linearly to production capacity. The scale-up from a smaller ultrasonic mixer to higher processing capacities is very simple since the ultrasonic mixing process can be completely linear scaled from your established process parameters. Up-scaling can be done by either installing a more powerful ultrasonic mixer unit or clustering several ultrasonicators in parallel.

High Amplitudes to Nanostructure Particles with High Efficiency

Hielscher Ultrasonics’ industrial ultrasonic processors can deliver very high amplitudes. Amplitudes of up to 200µm can be easily continuously run in 24/7 operation. For even higher amplitudes, customized ultrasonic sonotrodes are available. Ultrasonic sonotrodes (horns, probes) and reactors are autoclavable. The robustness of Hielscher’s ultrasonic equipment allows for 24/7 operation at heavy duty and in demanding environments.

Easy, Risk-free Testing

Ultrasonic processes can be completely linear scaled. This means every result that you have achieved using a lab or bench-top ultrasonicator, can be scaled to exactly the same output using the exactly same process parameters. This makes ultrasonication ideal for product development and subsequent implementation into commercial manufacturing.

Highest Quality – Designed and Manufactured in Germany

As a family-owned and family-run business, Hielscher prioritizes highest quality standards for its ultrasonic processors. All ultrasonicators are designed, manufactured and thoroughly tested in our headquarter in Teltow near Berlin, Germany. Robustness and reliability of Hielscher’s ultrasonic equipment make it a work horse in your production. 24/7 operation under full load and in demanding environments is a natural characteristic of Hielscher’s high-performance ultrasonicators.

You can buy Hielscher ultrasonic processors in any different size and exactly configured to your process requirements. From treating fluids in a small lab beaker to the continuous flow-through mixing of slurries and pastes on industrial level, Hielscher Ultrasonics offers a suitable high-performance homogenizer for you! Please contact us – we are glad to recommend you the ideal ultrasonic setup!

UP400St for molecularly imprinted polymer synthesis

UP400St – 400W powerful ultrasonic processor for sonochemical applications

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

Batch Volume Flow Rate Recommended Devices
1 to 500mL 10 to 200mL/min UP100H
10 to 2000mL 20 to 400mL/min UP200Ht, UP400St
0.1 to 20L 0.2 to 4L/min UIP2000hdT
10 to 100L 2 to 10L/min UIP4000hdT
n.a. 10 to 100L/min UIP16000
n.a. larger cluster of UIP16000

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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.

Literature / References