Continuous-flow manufacturing of essential antibiotic cefazolin: Flexible production while reducing costs

 

The antibiotic cefazolin is an essential drug according to the World Health Organization (WHO). It is usually produced via batch manufacturing, but this multistep process is time-consuming, wasteful and requires very specialized facilities.

 

Cefazolin is a broad-spectrum cephalosporin antibiotic mainly used for the treatment of skin bacterial infections and other moderate to severe bacterial infections in the lung, bone, joint, stomach, blood, heart valve, and urinary tract. The drug is effective against non-resistant forms of:

 

·         Staphylococcus aureus (including beta-lactamase producing strains)

·         Staphylococcus epidermidis

·         Streptococcus pyogenes,

·         Streptococcus agalactiae,

·         Streptococcus pneumoniae and other strains of streptococci

·         Escherichia coli

·         Proteus mirabilis

·         Klebsiella pneumoniae

 

Researchers have manufactured cefazolin using the continuous-flow method. This method is cheaper, quicker, less wasteful and more flexible in terms of how much drug can be produced when it is needed. As with most drugs, cefazolin is made via batch manufacturing, a step-by-step process enabling precise control at each stage. Due to the time frame, specially equipped and controlled space, and large amount of waste, production costs are not inexpensive and are particularly high when setting up new facilities.

 

An alternative to batch manufacturing is continuous-flow manufacturing. This method had not widely been used by drugmakers because it is more challenging to control the reactions taking place. However, researchers at the University of Tokyo have now developed a way to safely create cefazolin through continuous-flow manufacturing

 

Demand for this antibiotic fluctuates wildly and it is a drug that is better to not prepare too far in advance due to its instability. The benefit of the continuous-flow method is that it is easy to adjust the production volume as needed.

 

Continuous-flow manufacturing does not require pauses in between multiple individual steps, unlike the batch method. The researchers used two connected reactors to produce cefazolin from readily available commercial raw materials. The raw materials and reagents, which facilitate the reaction, were pumped into the first reactor, which looks like a coiled thin metal tube, before moving into a second reactor where another raw material was added. From there flowed the cefazolin.

 

The challenge was in optimising the environment inside the reactors, such as the temperature, transfer speed and mixing ratio of reagents, etc., to be able to obtain a high-purity product at the end, particularly due to the complex structure of cefazolin.

 

Many compounds can be synthesized by continuous-flow methods. By adopting this method, it is possible to produce a more stable drug supply, respond to rare diseases and disasters, and aid new drug development.

 

See:

 

Shoichi Sugita, Haruro Ishitani, Shū Kobayashi. A Practical and Convenient Synthesis of the Essential Antibiotic Drug Cefazolin under Sequential One-Flow Conditions. Bulletin of the Chemical Society of Japan, 2023; 96 (8): 744

 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)