Ultrasonic Synthesis of Pharma-Grade Chloroquine

Chloroquine seem to be a promising drug in the fight against the COVID-19 pandemic. Whilst chloroquine is a long-known, cheap drug, the supply must be significantly ramped up to fulfil the current need. Ultrasonic synthesis is a simple, safe and reliable process for the fast production of pharma-grade chloroquine. Linearly scaleable, it allows to produce large quantities in a highly controllable inline process.


Chloroquine and quinoline analogues can be ultrasonically synthesised.Chloroquine, chloroquine phosphate and hydroxychloroquine are both established drugs used as malaria treatment and malaria prophylaxis. The substances inhibit ACE2 glycosylation, a process in which the proteins in the virus’ envelope are biochemically transformed. Glycosylation is an important step during the viral infection of a cell. The chloroquine induced inhibition of glycosylation seems to prevent or reduce the infection rate by SARS-CoV-2 significantly.
What current research says:
“Chloroquine is also immunomodulatory, capable of suppressing the production and release of factors which mediate the inflammatory complications of viral diseases (tumor necrosis factor and interleukin 6). It is postulated that chloroquine works by altering ACE2 glycosylation and endosomal pH. Its anti-inflammatory properties may be beneficial for the treatment of SARS.” [Pang et al. 2020]
Prof. Didier Raoult from the Institut Hospitalo-Universitaire (IHU) in Marseille says about his first chloroquine trials: “We were able to ascertain that patients who had not received Plaquenil (the drug containing hydroxychloroquine) were still contagious after six days, but of those that had received Plaquenil, after six days, only 25% were still contagious.”

Whilst the pharmaceutical molecule chloroquine is not (yet) approved to treat patients suffering from COVID-19, research is underway and preliminary studies already have shown promise.

Advantages of Ultrasonic Synthesis of Pharmaceutical Molecules:

  • High-quality, high purity
  • High conversion rate
  • Rapid process
  • Linear scalability
  • Cost-effective
  • Green, environmental-friendly
Ultrasonic processor UIP2000hdT (2kW) with stirred pharma batch reactor

Ultrasonic homogenizer UIP2000hdT (2kW) with continuously stirred batch reactor

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Ultrasonic Synthesis of Chloroquine

Ultrasonic Synthesis of Chloroquine Derivatives

Since chloroquine is known for its delicacy against Zika virus, Barbosa-Lima et al. (2017) researched the synthesis of chloroquine derivatives to find even more efficient chloroquine molecules against Zika. N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives showed very promising results.
Barbosa-Lima et al. (2017) found that the ultrasonic synthesis of produced similar yields in comparison to the thermal reflux method but in significantly shorter times of 30-180 sec sonication compared to 30-180 min thermal reaction time.
The quinoline derivative, N-(2-((5-nitrofuran-2-yl)methylimino)ethyl)-7-chloroquinolin-4-amine, 40, was the most potent compound within this series, reducing ZIKV replication by 72% at 10 μM. Good activities were also obtained for other compounds, including those with aryl groups = phenyl, 4-fluorophenyl, 4-nitrophenyl, 2,6-dimethoxyphenyl, 3-pyridinyl and 5-nitrothien-2-yl. All of these molecules have been successfully synthesised via ultrasonication.

Ultrasonic Synthesis of Quinolones

Kowsari et al. (2011) synthesized certain quinolones by reacting isatin with aryl methyl ketones in the presence of basic ionic liquids in water. The reaction was conducted under ultrasound green synthetic conditions. The main advantages of this procedure are a green method, milder and shorter reaction time, and higher yields and selectivity without a transition metal catalyst.

Amid the COVID-19 pandemic Hielscher Ultrasonics prioritises all orders of the pharmaceutical sector. Please ask for prioritised order processing and expedited shipping!

High-Performance Ultrasonicators for Pharmaceutical Synthesis

Precise control over the ultrasonic process parameters by Hielscher Ultrasonics' intelligent softwareHielscher Ultrasonics’ systems are widely used in the pharmaceutical production to synthesise high-quality molecules and to formulate solid lipid nanoparticles and liposomes loaded with pharmaceutical substances, vitamins, antioxidants, peptides and other bioactive compounds. To meet its customers’ demands, Hielscher supplies ultrasonicators from the compact, yet powerful hand-held lab homogenizer and bench-top ultrasonicators to fully industrial ultrasonic systems for the production of high qualities of pharmaceutical substances and formulations. A broad range of ultrasonic sonotrodes and reactors are available to ensure an optimal setup for your pharmaceutical production. The robustness of Hielscher’s ultrasonic equipment allows for 24/7 operation at heavy duty and in demanding environments.
In order to enable our customers to fulfil Good Manufacturing Practices (GMP) and to establish standardised processes, all digital ultrasonicators are equipped with intelligent software for precise setting of the sonication parameter, continuous process control and automatic recording of all important process parameters on a built-in SD-card. High product quality depends on process control and continuously high processing standards. Hielscher ultrasonicators help you to monitor and standardise your process!

Scaling up

The high number of COVID-19 cases is a massive challenge to the health system including the pharmaceutical research and production. Whilst currently several drug substances are under investigation (in vitro and in vivo), from the moment a treatment therapy of COVID-19 patients has been established, a large number of drugs must be produced within a short period of time.
The ultrasonic synthesis of chloroquine and chloroquine derivatives is a fast, simple and safe process, which can be linearly scaled up from lab and pilot plant to full commercial production. Our well-trained and long-experienced staff will assist you technically from pilot trials to large quantity production.

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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Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for dispersion, emulsification and cell extraction.

High-power ultrasonic homogenizers from lab to pilot and industrial scale.


Facts Worth Knowing


Chloroquine is a member of the drug class 4-aminoquinoline. As a known antimalarial agent, chloroquine, shows antiviral effects against multiple viruses including HIV type 1, hepatitis B and HCoV-229E.
Chloroquine is a cheap and readily available generic drug. It has a high oral bioavailability and its pharmacology is well known.