(670g) Avibactam Tomilopil (AVT): Development of Spherical Crystallization Process for DS Isolation

Avibactam tomilopil (AVT) is an orally available prodrug of the beta-lactamase inhibitor avibactam that inhibits extended spectrum beta-lactamases to restore activity of beta-lactam antibiotics. AVT is intended to be co-administered with the cephalosporin antibiotic ceftibuten for the treatment of antibiotic-resistant urinary tract infections (1). AVT has unique challenges for isolation as this API is not completely crystalline – it is a disordered phase with low thermal onset. This makes it difficult to isolate API. Attributes such as powder flow and sticking propensity are necessary to understand for robust large scale API manufacture and drug product formulation development.

Here in, we present unique combination of predictive tools and experimental work, leading to the ~350 Kg successful scale up in the Pfizer pilot plant using spherical crystallization technique. This approach successfully leveraged solvent-antisolvent crystallization to achieve the better particle properties via spherical crystallization without need for milling; milling is not an option for this product due to the low thermal onset. The spherical crystallization has been studied heavily in academia and this work provides first proof of concept for applications of it on large scale production for mesophase material.

Reference

(1) NCT05554237, C. g. I. A Study to Learn About the Study Medicine Called CTB+AVP in Healthy Adult People. 2023. https://www.clinicaltrials.gov/study/NCT05554237 (accessed on 31st March 2025).